Carpal tunnel syndrome (CTS) is a prevalent hand disorder caused by compression of the median nerve at the wrist. It has an immense impact on national health care, worker productivity, and quality of life. CTS is commonly treated by a surgery that transects the transverse carpal ligament to decompress the median nerve. This surgical concept has existed for nearly a century without fundamental challenges, even though this procedure has a number of complications. Alternative treatments that do not release the ligament have been attempted, but their efficacy remains controversial due to lack of scientific and clinical evidence. Our search for an improved CTS treatment strategy has resulted in the serendipitous finding of a novel mechanism of median nerve decompression by applying transverse compression to the wrist to reshape and enlarge the tunnel space. Our approach to carpal tunnel expansion by shortening the carpal arch width is in contrast to existing methods that try to stretch the carpal tunnel outwards. Our finding and proof-of-concept hold significant potential to non-surgically treat CTS according to biomechanical principles. The overall goal of this proposed project is to design and develop a strategy of carpal tunnel manipulation that achieves treatment efficacy for CTS. Our central hypothesis is that our approach of biomechanical manipulation increases carpal tunnel area, thereby decompressing the median nerve and alleviating CTS symptoms. Three specific aims will be implemented to achieve the objective and confirm the hypothesis: (1) to determine the optimal biomechanical strategy of carpal tunnel manipulation such that the carpal tunnel cross-sectional area is effectively enlarged with the least amount of compressive force; (2) to investigate changes of carpal tunnel morphology, median nerve shape, and carpal tunnel pressure in response to the biomechanical manipulation in individuals with CTS; and (3) to demonstrate the clinical effectiveness of the biomechanical intervention in improving the neurophysiological deficiencies and symptoms associated with CTS. This project combines basic science and clinical translation, elucidating the underlying morphological and physiological mechanisms of the biomechanical intervention for a systematic and rigorous development of an evidence-based strategy for CTS treatment. Completion of this project will accelerate our realization of a novel strategy to biomechanically manage CTS without surgery.